The long term objective of this proposal is to address the role of IFN??signaling in the regulation of CD4 T cell responses during Mtb infection. Using a well-established mouse model of tuberculosis we will test the hypothesis that IFN??acts directly on CD4 T cells to regulate their differentiation, function and turnover during Mtb infection. We will compare Mtb-specific CD4 T cells that do not express a functional IFN??receptor, which are therefore are unable to respond to IFN??to wild type Mtb-specific CD4 T cells. This approach will allow us to address the direct effects of IFN??on CD4 T cells in an otherwise normal host environment (i.e., all other cell types express a functional IFN??receptor). In Aim 1 we will analyze expansion and activation of wild type and IFN??receptor-deficient Mtb-specific CD4 T cells in the lungs and relevant lymphoid tissues of Mtb infected mice. Aim 2 will address whether IFN??promotes contraction and/or differentiation of CD4 T cells during Mtb infection. PUBLIC HEALTH RELEVANCE. Tuberculosis is a major public health threat of worldwide proportions. The proposed studies will provide information essential for understanding the genesis of protective CD4 T cell responses during tuberculosis infections, so the data generated will be generally applicable to the development of vaccines and therapies designed to elicit CD4 T cell-mediated immunity in humans.